This invention relates to a novel series of 11-desoxy-15-thia-16-aryl-.omega.-tetranor prostaglandin compounds which have specific prostaglandin-like biological activity, the processes for making such compounds and synthetic intermediates employed in these processes.
The C.sub.20 unsaturated fatty acids, known as prostaglandins, form a large family of naturally-occurring compounds. These molecules may have as many as five asymmetric centers and are present in and evoke response from a diversity of biological tissues. An example of a particular species of the prostaglandin E genera is PGE.sub.2 pictured below. ##STR1##
According to the notation usually employed to describe the stereochemistry of prostaglandins, a heavy solid line represents the .beta. configuration. In a like manner, a dotted or hashed line represents the .alpha. configuration. Thus, the configuration of natural prostaglandin E.sub.2, pictured above, is .alpha. at carbon atoms 8, 11 and 15, and .beta. at carbon atoms 12 [S. Bergstrom, et al., Acta. Chem. Scand., 16, 601 (1962)].
By the same terminology, a wavy line represents a mixture of the two forms .alpha. and .beta.. Thus, PGE.sub.1 having the structure: ##STR2## represents a mmixture of the epimers ##STR3##
Three nomenclature systems are used to described various cogeners of prostaglandins. The first is a trivial system based upon the terms PGE, PGF and PGA. In this system, a compound of the present invention havin the structure ##STR4## would have the name 11-desoxy-13,14-dihydro-14-(benzylthio)-.omega.-hexanor PGF.sub.2.alpha..
The second system is based upon prostanoic acid which has the structure and position numbering: ##STR5##
In this nomenclature system, a compound of the present invention which has the structure ##STR6## would have the name 9-oxo-14-(benzylthio)-cis-5-.omega.-hexanorprostenoic acid.
The third form is the preferred, systematic nomenclature system. In this system, the compound immediately above is called 7-[5-oxo-2.beta.-(benzylthioethylenyl)cyclopent-1.alpha.-yl]hept-cis-5-eno ic acid.
The prostaglandins have several centers of asymmetry, and can exist in the racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory (D) and levorotatory (L) forms. As drawn above, each prostaglandin structure represents the particular optically active form or enantiomer which is analogous to or the same as the naturally occurring or "nat" prostaglandin. The mirror image or optical antipode of each of the above structures represents the other enantiomer of that compound and is termed the "ent" prostaglandin.
For instance, the optical antipode of 7-[5-oxo-2.beta.-(3.alpha.-hydroxyoct-trans-1-enyl)cyclopent-1.alpha.-yl]h eptanoic acid is drawn as: ##STR7## and is called 7-[5-oxo-2.alpha.-(3.beta.-hydroxyoct-trans-1-enyl)cyclopent-1.beta.-yl]-h eptanoic acid or "ent" 11-desoxy PGE.sub.1.
It is a fact that chemical experimentation on either member of an enantiomeric pair or upon a mixture of the two will produce the same and identical results.
The natural prostaglandins and many of their derivatives such as the esters, acylates, and pharmacologically acceptable salts, are extremely potent inducers of various biological responses [D. E. Wilson, Arch. Intern. Med., 133 (29) 1974)] in tissues composed of smooth muscle such as those of the cardiovascular, pulmonary, gastrointestinal and reproductive systems; in cellular tissues such as those of the central nervous, hematologic, reproductive, gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and adipose systems and also operate as mediators in the process of homeostasis. With such a wide range of responses, it is apparent that the prostaglandins are involved in basic biological processes of the cell. Indeed, this basic implication of prostaglandins is supported by the fact that they can be found in cellular tissue of all mammals and numerous other animals.
Often on such a cellular level the actions of closely related natural prostaglandins may be opposite. For instance, the effect of PGE.sub.2 on human platelets is enhancement of aggregation while that of PGE.sub.1 is inhibition of aggregation.
Such contrasting effects may also be observed at the tissue level. For instance, in vivo PGE.sub.2 action on the cardiovascular system of mammals manifests itself by causing hypotension while the in vivo action of PGF.sub.2.alpha. is hypertension [J. B. Lee, Arch. Intern. Med., 133 56 (1974)]. However, at present it is difficult to predict a specific biological action of a group of structurally related prostaglandins by considering the relationshp between it and another group of prostaglandins whose pharmacology is known. For instance, while the cardiovascular actions of PGE.sub.2 and PGF.sub.2.alpha. are opposite as described above, their in vivo and in vitro action on mammalian uterine smooth muscle is the same and is stimulatory (causes contraction) [H. R. Behrman, et al., Arch. Intern. Med., 133 77 (1974)].
In the preparation of synthetic pharmaceutical agents, among the principal objects is the development of compounds which are highly selective in their pharmacological activity and which have an increased duration of activity over their naturally occurring relatives. In a series of compounds similar to the naturally-occurring prostaglandins, increasing selectivity of a single compound usually involves the enhancement of one prostaglandin-like physiological effect and the diminution of the others. The potential benefits of this selectivity are manifold, for example, a decrease in the severe side effects such as diarrhea and emesis which are frequently observed following administration of the natural prostaglandins. A divorce of cardiovascular and bronchodilator activity which are both embraced by natural prostaglandins also would have obvious medicinal potential. Recent developments directed toward an increase of biological selectivity include the 11-desoxy prostaglandins [N. H. Anderson, Arch. Intern. Med., 133, 30 (1974) Review] 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted- - pentanorprostaglandins (M. R. Johnson et al., U.S. Pat. No. 3,932,389) where certain modifications are cited as producing selective vasodilator, antiulcer, antifertility, bronchodilator and antihypertensive properties and N-acyl or N-sulfonyl prostaglandin carboxamides (U.S. Pat. No. 3,954,741).
However, present in all of these synthetic prostaglandin pharmaceutical agents is the C15 hydroxyl group. It has long been known that one of the primary routes of metabolism and deactivation of prostaglandins is enzymatic oxidation of the C15 hydroxyl group to a C15 keto group. [T. O. Oesterling, et al., J. Pharm. Sci., 61, 1861 (1972)]. The product of this enzymatic transformation is not characterized by the breadth of physiological effects of natural prostaglandins and illustrates the importance of the C15 hydroxyl for prostaglandin biological activity [N. H. Anderson, et al., Arch. Intern. Med., 133, 30 (1974)]. This importance is also aptly demonstrated by the attenuation of biological activity when the C11 and C15 hydroxyls are completely removed. In a biological test, gastric acid secretion, which has direct relation to the biological activity of the compounds of the present invention, 11,15-bisdesoxy-13,14-dihydro-.omega.-trisnor PGE.sub.1 had significantly less activity than PGE.sub.1 [J. F. Poletto, et al., J. Med. Chem., 18, 359 ( 1975)]. Thus, it has surprisingly been discovered that the compounds of the present invention, which have neither the C11 nor C15 hydroxyl groups so essential for prostaglandin biological activity, have potent and selective prostaglandin-like biological activity.